Benveniste et al. found a factor in 1972 which strongly induced platelet aggregation from rabbit basophils. This factor was named platelet-activating factor (hereinafter referred to simply as PAF). Hanahan et al. identified the factor in 1980 as a phosphoglyceride of the alkyl ether type having an acetyl group in the 2-position, i.e. 1-O-hexadecyl or octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine.
The physiological roles of PAF have been intensively investigated, and it is known that PAF is an important factor in various physiological reactions, including platelet aggregation, reduction in blood pressure, immediate allergic reaction, contraction of smooth muscle, inflammation, pain, edema, and alteration in the respiratory and circulatory systems.
Therefore, PAF-antagonistic activity-possessing compounds are very useful for treating various PAF-induced diseases, such as inflammatory diseases, allergic diseases, anaphylatic shocks, septic shocks, vascular diseases as DIC, myocardinal diseases, asthma, pulmonary edema, and adult respiratory diseases.
Compounds useful as therapeutic and prophylactic agents for cardiovascular diseases, such as, myocardial contiactility impairment, thrombocytopenia, hypotension, anaphylaxis shock or endotoxin shock are disclosed in J. Pharmacol. Exp. Ther., 1985, 232, 156; Kidney Int., 1986, 29, 469; Pharmacol. Res. Commun., 1986, 18(suppl), 139, 173; Circulation, 1985, 72, 713; Prostaglandins, Leukotrienes and Lipoxins, Plenum Press, New York, 1985, p.301; Eur. J. Pharmacol., 1984, 98, 357; Annu. Rev. Pharmacol. Toxicol., 1987, 27, 301; and Platelet-Activating Factor and Related Lipid Mediations, Plenum Press, New York, 1987, p.403. Compounds useful as therapeutic and prophylactic agents for organ transplantation are disclosed in Transplantation, 1986, 42, 86; Eur. J. Clin. Invest., 1987, 17, 7; and Thromb. Haemostasis, 1987, 57, 125. Compounds useful as therapeutic and prophylactic agents for inflammatory, edema and immunophathological conditions are disclosed in Inflammation-Basic Principles and Clinical Correlates, Raven Press, New York, 1988, p.13; Platelet-Activating Factor and Cell Immunology, Karger, Basel, 1988, vols 1 and 2; Drugs Future, 1988, 13, 137; and Immunol. Today, 1987, 8, 345. Compounds useful as therapeutic and prophylactic agents for asthma and respiratory conditions are disclosed in Trends Pharmacol. Sci., 1987, 8, 285; Drugs, 1988, 35, 93; Agents Actions, 1984, 15, 636; Eur. J. Respir. Dis., 1986, 68(suppl. 144), 163; Lancet, 1986, 2, 189; and Int. Arch. Allergy Appl. Immunol., 1987, 82, 57. Compounds useful as therapeutic and prophylactic agents for pulmonary hypertension and adult respiratory distress syndrome (ARDS) are disclosed in Chest, 1983, 83 (suppl.), 785; Agents Actions, 1981, 11, 567; and Prostaglandins, 1983, 26, 457. Compounds useful as therapeutic and prophylactic agents for ischemia are disclosed in Platelet-Activating Factor and Structurally Related Alkyl Ether Lipids, American Oil Chemist's Society, p.1236-1242, 1991; Biochem. Biophys. Res. Commun., 149, p.580-587, 1987; J. Neurochem., 151, p.88-109, 1988; Ann. N.Y. Acad. Sci., 559, p.1-16, 1989; and Pharmacol. Rev., 39, p.97-145, 987. Compounds useful as therapeutic and prophylactic agents for ulcergenesis and gastrointestinal alterations are disclosed in Nature (London), 1986, 319, 54. Compounds useful as therapeutic and prophylactic agents for lethal anaphylatic shock are disclosed in Br. J. Pharmacol., 1984, 83, 125; Br. J. Pharmacol., 1983, 79, 595; Br. J. Pharmacol., 1987, 90, 203; and Prostaglandins, 1985, 30, 545.
Under these circumstances, investigations have been made on compounds having anti-PAF activity. Among these compounds, ginkgolide compounds (A, B, C, M and J), which are terpenoid compounds from the roots and leaves of the Ginkgo tree, have exhibited the PAF antagonistic activity described above. However, these compounds possess certain deficiencies in the areas of effects on the central nervous system, potency, effectiveness by oral administration, water solubility, effectiveness by intravenous administration and duration of activity. Therefore, there is a need for potent PAF-antagonistic ginkgolide compounds which possess not only effectiveness by oral administration, long lasting effect, water solubility and effectiveness by intravenous administration, but also less inhibitory effects on the central nervous system.
Accordingly, the present inventors have conducted long term investigations and studies on ginkgolide derivatives which have not only excellent PAF-inhibiting activity, but also excellent physiological activity. The present invention has been accomplished based on these findings.